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Inflammation Targets Specific Organs for Cancer in Carriers of BRCA1/2 Pathway Mutations

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Inflammation Targets Specific Organs for Cancer in Carriers of BRCA1/2 Pathway Mutations Inflammation targets specific organs for cancer in carriers of BRCA1/2 pathway mutations Bernard Friedenson Department of Biochemistry and Molecular Genetics College of Medicine University Illinois Chicago 900 South Ashland Ave Chicago, IL 60607 Email: [email protected] Nature Precedings : hdl:10101/npre.2010.4225.1 Posted 18 Feb 2010 1 Abstract Women who inherit a defective BRCA1 or BRCA2 gene have risks for breast/ovarian cancer that are so high and apparently so selective that many mutation carriers choose to have the most likely targets for cancer surgically removed. Recent research has focused on better methods of treating such seemingly unavoidable hereditary cancers. Prevention has received much less attention so a positive test result for a cancer gene leaves carriers with very limited options. In order to prevent BRCA1/2 related cancers, it may be important to understand why they seem to occur only in certain characteristic organs. Results here show that mutations in a pathway depending on BRCA1/2 gene products magnify cancer risks from chronic infection and inflammation, making them especially important in selecting the site where hereditary cancer develops. Control- ling chronic infections and inflammation may be a helpful option to prevent or delay cancers in muta- tion carriers. Introduction Women who inherit a defective BRCA1 or BRCA2 gene have risks for breast/ovarian cancer that are so high and apparently so selective that many mutation carriers choose to have the most likely targets for cancer surgically removed [1-7]. Recent research has focused on better methods of treating the cancers that seem unavoidable. Prevention has received much less attention so a posi- tive test result for a cancer related mutation leaves carriers with very limited options. In order to prevent BRCA1/2 related cancers, it may be important to understand why they seem to occur only in certain characteristic organs. Why would cancer just attack breasts and Nature Precedings : hdl:10101/npre.2010.4225.1 Posted 18 Feb 2010 ovaries when every cell with a nucleus contains the same mutation? Functionally, both BRCA genes are general cell requirements because they encode products essential for checkpoint controls and for DNA repairs. How does inheritance of a defect in general cell requirements lead to cancers in specific target organs? Here the possibility is tested that infection and chronic inflammation direct inherited cancers to specific organ targets. Evidence is overwhelming that chronic inflammation underlies many can- cers and that some chronic infections can direct cancer to a specific organ. For example, hepatitis viruses target the liver for cancer because the liver has receptors for hepatitis viruses. Hepatitis B and C viruses do not cause cancer unless chronic inflammation follows infection, leading to DNA breaks [8, 9]. Many normal individuals recover and never develop liver cancer. Inherited cancer related mutations are rare, making risks from chronic inflammatory condi- tions difficult to study. Results from epidemiology were used to approach this problem. Risks for 2 cancers associated with inflammation in a specific organ were statistically combined from eleven published studies of known or likely mutation carriers. The resulting statistical summaries of cancer relative risks included over 25,000 carriers of any testable mutation in DNA damage responses de- pending on BRCA1 and BRCA2 gene products. The rarity of BRCA1/2 mutations made it necessary to include all testable components in the subroutine that depends on functional BRCA1 and BRCA2 proteins. Figure 1 shows an approximate arrangement of the testable components in a model subroutine within the DNA damage response [10, 11] Strong evidence supports the idea that inactivating a gene encoding any of these compo- nents causes genomic instability and increases cancer risks. All the components in the model partici- pate in DNA damage responses that can be induced by reactive oxygen products from inflammatory processes. These responses are double strand break repair by homologous recombination, repair of collapsed or stalled DNA replication forks, and prevention of hypersensitivity to DNA cross-linking agents. Cancer genome sequences rarely inactivate more than one gene in the same sub-routine. Fanconi anemia (FA), ataxia-telangiectasia (A-T) and BRCA deficiency are hereditary can- cer prone diseases caused by inactivation of one gene in the pathway containing BRCA1/2. In each condition there are increased numbers of chromosome breaks, large rearrangements, and/or regional gains and losses in chromosomes [Fig. 1,12, 13]. Multiple steps in the repair of interstrand cross-links can fail when the FA pathway is compromised. A-T patients have elevated risks for DNA damage in tissues undergoing inflammation [14] and FA patients over-express inflammatory genes and proteins [15]. Cells that are deficient in any one of eight FA core complex proteins are defective in monou- biquitylation of FANCD2 and FANCI. This defect causes chromosome breakages and FA hypersensi- tivity to DNA cross-linking agents. (See footnote to Fig 1). Here, mutation carriers were found to have strikingly increased risks for cancers connected to known chronic inflammatory infections such as liver cancer, cervical cancer and stomach can- Nature Precedings : hdl:10101/npre.2010.4225.1 Posted 18 Feb 2010 cer. Risks increase hundreds of times in homozygotes and up to several-fold in heterozygotes. For BRCA1/2 related breast and ovarian cancers, cancer prevention data and evidence of immune re- sponses suggest that chronic inflammation helps target these organs. Inflammation also disrupts nor- mal cellular organization and architecture, further favoring cancer. Identifying and controlling chronic infections and inflammation may delay or prevent some hereditary cancers in mutation carriers. Materials and Methods Identification of studies. Epidemiologic data exists describing effects of mutation of numerous components within the DNA damage response network [16]. In order to reduce bias, explicit procedures [17] were used to systematically identify, appraise, summarize and statistically ag- gregate relevant studies. Information sources. PubMed and Google Scholar databases were systematically searched 3 3 DNA Double Strand Break v acti atio in n RAD50 CHEK2 MRE11 ATM Nbs1 BRCA1 Fanconi anemia Chromosome protein J Other inactiva Fanconi Rearrangements, tion Chromosome anemia Regional Gains, proteins Rearrangements, Losses Regional Gains, BRCA2 Losses FANCD1 Homologous recombination “Error-free” DNA repair Fig 1. Simplified model for a double strand break repair subroutine emphasizing components that have epidemiologic studies measuring risks for multiple cancers beyond breast and ovarian cancer. Inactivation of ATM, Fanconi genes, or BRCA1/2 genes in hereditary conditions causes large chromo- somal rearrangements, losses or gains of sections of chromosomes [11-14]. BRCA2 is the same as Fanconi component D1. FA protein J is the same as BRIP1 (BRCA1 interacting protein 1). Mutation of genes encoding any of numerous pathway components produces cancers in an overlapping distri- bution of organs. For example, mutations in NBS1, RAD50, ATM, BRCA1, BRCA2, CHEK2, FANCJ (BRIP1), or FANCN (PALB2) have each been associated with increased breast cancer risks. Not shown are numerous interactions with other proteins and relationships to cell cycle checkpoints (see footnote). The results reported here do not require that the pathway be linear and do not preclude participation by hormones. Nature Precedings : hdl:10101/npre.2010.4225.1 Posted 18 Feb 2010 Footnote Details of this outlined pathway are still emerging but many publications place FA pro- teins in the DNA damage network including BRCA1 and BRCA2 with activation by ATM and Rad3 related (ATR) kinase [e. g. 74, 75, 11]. Of the 13 FA proteins identified, eight of these, including FANC-A, -B, -C, -E, -F, -G, -L, and -M, form a multi-subunit nuclear FA core complex. In response to replication stress, the FA core complex promotes the monoubiquitylation of the FANCD2-FANCI heterodimer, which triggers their relocalization to sites of replication stress. Cells that are deficient in any one of the eight core complex proteins are defective in monoubiquitylation of FANCD2 and FANCI. The FA core complex acts as the E3 ligase for FANCD2 and FANCI. Any mutations that disrupt ubiquitylation of FANCD2 cause FA chromosome breakages and FA hypersensitivity to DNA cross-linking agents. The other FA factors, FANCD1/BRCA2, FANCJ/BRIP, and FANCN/PALB2, are believed to function downstream of the FA core complex, possibly in the regulation of homolo- gous recombination, also playing essential roles in lesion repair and replication fork recovery [74]. BRCA1 is essential for the formation of nuclear foci, believed to be sites of DNA repair. 4 up to 2010, for original epidemiologic studies of non-breast, non-ovarian cancers vs. any defect in the model pathway in Fig. 1. 1250 articles published in the past 50 years were retrieved and copied to a database to facilitate computer searching and review. Many bibliographies were also reviewed for ad- ditional relevant references that may have been missed. No language restrictions were imposed. Models for inflammation related cancers. From these initial surveys, results were summarized for five cancers that have widely accepted and well-known links to chronic infection as follows. Group 1: liver cancer associated with viral hepatitis such as hepatitis
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